Method and simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists

ABSTRACT

This invention relates to a method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist such as morphine and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist. The method of the present invention comprises administering to a subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist such as morphine and an amount of an excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 09/094,977, filed Jun.16, 1998, now U.S. Pat. No. 6,096,756, which is a continuation ofapplication Ser. No. 08/759,590, filed Dec. 3, 1996, now U.S. Pat. No.5,767,125, which is a continuation-in-part of application Ser. No.08/276,966, filed Jul. 19, 1994, which issued as U.S. Pat. No. 5,512,578and reissued as U.S. Reissue Pat. No. 36,547, which is acontinuation-in-part of application Ser. No. 08/097,460, filed Jul. 27,1993, now U.S. Pat. No. 5,472,943, which is a continuation-in-part ofapplication Ser. No. 07/947,690, filed Sep. 19, 1992, now abandoned, thecontents of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

This invention relates to a method of enhancing the analgesic(inhibitory) effects of bimodally-acting opioid agonists, includingmorphine, codeine and other-clinically used opioid analgesics, while atthe same time attenuating anti-analgesia, physical dependence,tolerance, hyperexcitability, hyperalgesia, and other undesirable(excitatory) side effects typically caused by chronic use ofbimodally-acting opioid agonists.

“Bimodally-acting opioid agonists” are opioid agonists that bind to andactivate both inhibitory and excitatory opioid receptors on nociceptiveneurons which mediate pain. Opioid analgesia results from activation byopioid agonists of inhibitory opioid receptors on neurons in thenociceptive (pain) pathways of the peripheral and central nervoussystems. The undesirable side effects, including anti-analgesic actions,hyperexcitability and hyperalgesia, the development of physicaldependence, and some types of tolerance result from sustained activationby bimodally-acting opioid agonists of excitatory opioid receptors onneurons in the nociceptive (pain) pathways of the peripheral and centralnervous systems.

In the instant invention, a very low dose of a selective excitatoryopioid receptor antagonist, an opioid which binds to and acts as anantagonist to excitatory but not inhibitory opioid receptors onnociceptive neurons which mediate pain, is combined with a dose of abimodally-acting opioid agonist so as to enhance the degree of analgesia(inhibitory effects) and attenuate the undesired side effects(excitatory effects).

BACKGROUND OF THE INVENTION

Morphine or other bimodally-acting opioid agonists are administered torelieve severe pain due to the fact that they have analgesic effectsmediated by their activation of inhibitory opioid receptors onnociceptive neurons (see North, Trends Neurosci., Vol. 9, pp. 114-117(1986) and Crain and Shen, Trends Pharmacol. Sci., Vol. 11, pp. 77-81(1990)).

However, morphine and other bimodally-acting opioid agonists alsoactivate opioid excitatory receptors on nociceptive neurons, whichattenuate the analgesic potency of the opioids and result in thedevelopment of physical dependence and increased tolerance (see Shen andCrain, Brain Res., Vol. 597, pp. 74-83 (1992)), as well ashyperexcitability, hyperalgesia and other undesirable (excitatory) sideeffects. As a result, a long-standing need has existed to develop amethod of both enhancing the analgesic (inhibitory) effects ofbimodally-acting opioid agonists and blocking or preventing undesirable(excitatory) side effects caused by such opioid agonists. The presentinvention satisfies this need.

SUMMARY OF THE INVENTION

This present invention is directed to a method for selectively enhancingthe analgesic potency of a bimodally-acting opioid agonist andsimultaneously attenuating anti-analgesia, hyperalgesia,hyperexcitability, physical dependence and/or tolerance effectsassociated with the administration of the bimodally-acting opioidagonist. The method comprises administering to a subject an analgesic orsub-analgesic amount of a bimodally-acting opioid agonist and an amountof an excitatory opioid receptor antagonist effective to enhance theanalgesic potency of the bimodally-acting opioid agonist and attenuatethe anti-analgesia, hyperalgesia, hyperexcitability, physical dependenceand/or tolerance effects of the bimodally-acting opioid agonist.

The present invention also provides a method for treating pain in asubject comprising administering to the subject an analgesic orsub-analgesic amount of a bimodally-acting opioid agonist and an amountof an excitatory opioid receptor antagonist effective to enhance theanalgesic potency of the bimodally-acting opioid agonist and attenuateanti-analgesia, hyperalgesia, hyperexcitability, physical dependenceand/or tolerance-effects of the bimodally-acting opioid agonist.

The present invention further provides a method for treating an opiateaddict comprising administering to the opiate addict an amount of anexcitatory opioid receptor antagonist either alone or in combinationwith a bimodally-acting opioid agonist effective to attenuate physicaldependence caused by a bimodally-acting opioid agonist and enhance theanalgesic potency of a bimodally-acting opioid agonist.

Finally, the present invention provides a composition comprising ananalgesic or sub-analgesic amount of a bimodally-acting opioid agonistand an amount of an excitatory opioid receptor antagonist effective toenhance the analgesic potency of the bimodally-acting opioid agonist andattenuate the anti-analgesia, hyperalgesia, hyperexcitability, physicaldependence and/or tolerance effects of the bimodally-acting opioidagonist in a subject administered the composition.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 represents the structural formulae of the bimodally-acting opioidagonist morphine and the excitatory opioid receptor antagonistsnaloxone, naltrexone and nalmefene. Naltrexone is theN-cyclopropylmethyl congener of naloxone. Nalmefene is the 6-methylenederivative of naltrexone (Hahn, E. F., et al. J. Med. Chem. 18:259-262(1975)).

FIG. 2 represents the direct inhibitory effect of etorphine on theaction potential duration (APD) of nociceptive types of sensory neuronsand the blocking effect of etorphine on the excitatory response (APDprolongation) elicited by morphine. Acute application of low (pM-nM)concentrations of etorphine to naive dorsal root ganglion (DRG) neuronselicits dose-dependent, naloxone-reversible inhibitory shortening of theAPD. In contrast, morphine and other bimodally-acting opioid agonistselicit excitatory APD prolongation at these low concentrations which canbe selectively blocked by <pM levels of etorphine, resulting inunmasking of potent inhibitory APD shortening by nM morphine.

FIG. 3 represents dose-response curves of different opioids, showingthat etorphine and dihydroetorphine elicit only inhibitorydose-dependent shortening of the APD of DRG neurons at allconcentrations tested (fM-μM). In contrast, dynorphin A (as well asmorphine and other bimodally-acting opioids) elicit dose-dependentexcitatory APD prolongation at low concentrations (fM-nM) and requiresmuch higher concentrations (about 0.1-1 μM) to shorten the APD, therebyresulting in a bell-shaped, dose-response curve.

FIGS. 4A and 4B represent the selective blocking of excitatoryAPD-prolonging effects elicited by morphine in DRG neurons byco-administration of a low (pM) concentration of diprenorphine, therebyunmasking potent dose-dependent inhibitory APD shortening by lowconcentrations of morphine (comparable to the inhibitory potency ofetorphine). In contrast, co-treatment with a higher (nM) concentrationof DPN blocks both inhibitory as well as excitatory opioid effects.

FIG. 5 represents similar selective blocking of excitatoryAPD-prolonging effects elicited by morphine in DRG neurons whenco-administered with a low (pM) concentration of naltrexone, therebyunmasking potent inhibitory APD shortening by low concentrations ofmorphine. In contrast, a higher (μM) concentration of naltrexone blocksboth inhibitory as well as excitatory opioid effects.

FIG. 6 represents the assay procedure used to demonstrate that selectiveantagonists at excitatory opioid receptors prevents development oftolerance/dependence during chronic co-treatment of DRG neurons withmorphine.

FIG. 7 represents a comparison of the antinociceptive potency of 1 mg/kgmorphine administered (i.p.) to mice alone, 10 ng/kg naltrexoneadministered (i.p.) to mice alone, and a combination of 1 mg/kg morphineand 10 ng/kg naltrexone administered (i.p.) to mice. Shown are thetime-response curves for 1 mg/kg morphine (×); 1 mg/kg morphine and 10ng/kg naltrexone (NTX) (□); 10 ng/kg naltrexone (▪), in a warm-water(55° C.) tail-flick test. Twenty-five mice were used per dosing group(10 animals for NTX alone). Injection of 10 ng of NTX per kg alone didnot elicit analgesic effects. **, Statistically significant differencebetween individual morphine vs. morphine plus naltrexone time points:P<0.01.

FIG. 8 represents a comparison of the percentage of mice showingnaloxone-precipitated withdrawal jumping (i) 3-4 hours after injectionwith morphine alone (100 mg/kg, s.c.), and morphine (100 mg/kg, s.c.)plus naltrexone (10 μg/kg, s.c.) (acute physical dependence assay); and(ii) 4 days after increasing daily injections with morphine alone (20-50mg/kg, s.c.), and morphine (20-50 mg/kg, s.c.) plus naltrexone (10μg/kg, s.c.) (chronic physical dependence assay). **, Statisticallysignificant difference from control morphine alone group: P<0.01; **,P<0.001.

FIG. 9 represents a comparison of the antinociceptive potency ofmorphine administered (i.p.) to mice alone, and morphine administered(i.p.) to mice in combination with various ultra-low doses of nalmefene(NMF). Shown are the time-response curves for 3 mg/kg morphine (); 3mg/kg morphine and 100 ng/kg nalmefene (□); 3 mg/kg morphine and 10ng/kg nalmefene (×); and 3 mg/kg morphine and 1 ng/kg nalmefene (⋄) in awarm-water (55° C.) tail-flick test. Ten mice were used per dosinggroup.

FIG. 10 represents a comparison of the percentage of mice showingnaloxone-precipitated withdrawal jumping 4 hours after injection (acutephysical dependence assay) with a 100 mg/kg (s.c.) dose of morphine(Mor) alone or in combination with 1 or 10 μg/kg (s.c.) dose ofnalmefene (NMF) or 10 μg/kg (s.c.) dose of naltrexone (NTX). Additionalinjections of nalmefene (1 or 10 μg/kg, s.c.) or naltrexone (10 μg/kg,s.c.) were made 90 minutes after the initial injections. **,Statistically significant difference from control morphine alone group:P<0.01; **, P<0.001.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “opioid” refers to compounds which bind tospecific opioid receptors and have agonist (activation) or antagonist(inactivation) effects at these receptors, such as opioid alkaloids,including the agonist morphine and the antagonist naloxone, and opioidpeptides, including enkephalins, dynorphins and endorphins. The term“opiate” refers to drugs derived from opium or related analogs.

“Bimodally-acting opioid agonists” are opioid agonists that bind to andactivate both inhibitory and excitatory opioid receptors on nociceptiveneurons which mediate pain. Activation of inhibitory receptors by saidagonists causes analgesia. Activation of excitatory receptors by saidagonists results in anti-analgesia, hyperexcitability, hyperalgesia, aswell as development of physical dependence, tolerance and otherundesirable side effects.

Bimodally-acting opioid agonists suitable for use in the presentinvention may be identified by measuring the opioid's effect on theaction potential duration (APD) of dorsal root ganglion (DRG) neurons intissue cultures. In this regard, bimodally-acting opioid agonists arecompounds which elicit prolongation of the APD of DRG neurons at pM-nMconcentrations (i.e. excitatory effects), and shortening of the APD ofDRG neurons at μM concentrations (i.e. inhibitory effects). Suitablebimodally-acting opioid agonists include but are not limited tomorphine, codeine, fentanyl analogs, pentazocine, buprenorphine,methadone, enkephalins, dynorphins, endorphins and similarly actingopioid alkaloids and opioid peptides. For purposes of treating pain,morphine and codeine are preferred. Buprenorphine and methadone arepreferred for treating opioid addiction.

“Excitatory opioid receptor antagonists” are opioids which bind to andact as antagonists to excitatory but not inhibitory opioid receptors onnociceptive neurons which mediate pain. That is, excitatory opioidreceptor antagonists are compounds which bind to excitatory opioidreceptors and selectively block excitatory opioid receptor functions ofnociceptive types of DRG neurons at 1,000 to 10,000-fold lowerconcentrations than are required to block inhibitory opioid receptorfunctions in these neurons.

Excitatory opioid receptor antagonists suitable for use in the presentinvention may also be identified by measuring their effect on the actionpotential duration (APD) of dorsal root ganglion (DRG) neurons in tissuecultures. In this regard, excitatory opioid receptor antagonists arecompounds which selectively block prolongation of the APD of DRG neurons(i.e. excitatory effects) but not the shortening of the APD of DRGneurons (i.e. inhibitory effects) elicited by a bimodally-acting opioidreceptor agonist. Suitable excitatory opioid receptor antagonists of theinvention include nalmefene, naltrexone, naloxone, etorphine anddihydroetorphine, as well as similarly acting opioid alkaloids andopioid peptides. Preferred excitatory opioid receptor antagonists arenalmefene and naltrexone because of their longer duration of action ascompared to naloxone and their greater bioavailability after oraladministration.

The bimodally-acting opioid agonists and the excitatory opioid receptorantagonists for use in the present invention may in the form of freebases or pharmaceutically acceptable acid addition salts thereof.Examples of suitable acids for salt formation include but are notlimited to methanesulfonic, sulfuric, hydrochloric, glucuronic,phosphoric, acetic, citric, lactic, ascorbic, maleic, and the like.

The excitatory opioid receptor antagonist alone, or in combination withthe bimodally-acting opioid agonist, may be administered to a human oranimal subject by known procedures including but not limited to oral,sublingual, intramuscular, subcutaneous, intravenous, and transdermalmodes of administration. When a combination of these compounds areadministered, they may be administered together in the same composition,or may be administered in separate compositions. If the bimodally-actingopioid agonist and the excitatory opioid receptor antagonist areadministered in separate compositions, they may be administered bysimilar or different modes of administration, and may be administeredsimultaneously with one another, or shortly before-or after the other.

The bimodally-acting opioid agonists and the excitatory opioid receptorantagonists may be formulated in compositions with a pharmaceuticallyacceptable carrier. The carrier must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. Examples of suitablepharmaceutical carriers include lactose, sucrose, starch, talc,magnesium stearate, crystalline cellulose, methyl cellulose,carboxymethyl cellulose, glycerin, sodium alginate, gum arabic, powders,saline, water, among others. The formulations may conveniently bepresented in unit dosage and may be prepared by methods well-known inthe pharmaceutical art, by bringing the active compound into associationwith a carrier or diluent, as a suspension or solution, and optionallyone or more accessory ingredients, e.g. buffers, flavoring agents,surface active agents, and the like. The choice of carrier will dependupon the route of administration.

For oral and sublingual administration, the formulation may be presentedas capsules, tablets, powders, granules or a suspension, withconventional additives such as lactose, mannitol, corn starch or potatostarch; with binders such as crystalline cellulose, cellulosederivatives, acacia, corn starch or gelatins; with disintegrators suchas corn starch, potato starch or sodium carboxymethyl-cellulose; andwith lubricants such as talc or magnesium stearate.

For intravenous, intramuscular, or subcutaneous administration, thecompounds may combined with a sterile aqueous solution which ispreferably isotonic with the blood of the recipient. Such formulationsmay be prepared by dissolving solid active ingredient in watercontaining physiologically compatible substances such as sodiumchloride, glycine, and the like, and having a buffered pH compatiblewith physiological conditions to produce an aqueous solution, andrendering said solution sterile. The formulations may be present in unitor multi-dose containers such as sealed ampoules or vials.

For transdermal administration, the compounds may be combined with skinpenetration enhancers such as propylene glycol, polyethylene glycol,isopropanol, ethanol, oleic acid, N-methylpyrrolidone, and the like,which increase the permeability of the skin to the compounds, and permitthe compounds to penetrate through the skin and into the bloodstream.The compound/enhancer compositions also may be combined additionallywith a polymeric substance such as ethylcellulose, hydroxypropylcellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, and the like,to provide the composition in gel form, which can be dissolved insolvent such as methylene chloride, evaporated to the desired viscosity,and then applied to backing material to provide a patch.

When the excitatory opioid receptor antagonist is used in combinationwith the bimodally-acting opioid agonist, the amount of thebimodally-acting opioid agonist administered may be an analgesic orsub-analgesic amount. As used herein, an “analgesic” amount is amount ofthe bimodally-acting opioid agonist which causes analgesia in a subjectadministered the bimodally-acting opioid agonist alone, and includesstandard doses of the agonist which are typically administered to causeanalgesia (e.g, mg doses). A “sub-analgesic” amount is an amount whichdoes not cause analgesia in a subject administered the bimodally-actingopioid agonist alone, but when used in combination with the excitatoryopioid receptor antagonist, results in analgesia. The amount of theexcitatory opioid receptor antagonist is an amount effective to enhancethe analgesic potency of the bimodally-acting opioid agonist andattenuate the anti-analgesia, hyperalgesia, hyperexcitability, physicaldependence and/or tolerance effects of the bimodally-acting opioidagonist. Based on studies of nociceptive DRG neurons in culture and invivo mouse studies, the amount of the excitatory opioid receptoradministered may be between about 1000 and about 10,000,000 fold less,and preferably between about 10,000 and 1,000,000 fold less than theamount of the bimodally-acting opioid agonist administered. The optimumamounts of the bimodally-acting opioid agonist and the excitatory opioidreceptor antagonist administered will of course depend upon theparticular agonist and antagonist used, the carrier chosen, the route ofadministration, and the pharmacokinetic properties of the subject beingtreated.

When the excitatory opioid receptor antagonist is administered alone(i.e. for treating an opioid addict), the amount of the excitatoryopioid receptor antagonist administered is an amount effective toattenuate physical dependence caused by a bimodally-acting opioidagonist such as morphine and enhance the analgesic potency of thebimodally-acting opioid agonist. That is, the amount of the excitatoryopioid receptor antagonist is an amount which blocks the excitatoryeffects (i.e. physical dependence) of the bimodally-acting opioidagonist without blocking the inhibitory effects (i.e. analgesic effects)of the bimodally-acting opioid agonist. This amount is readilydeterminable by one skilled in the art.

The present invention is described in the following examples which areset forth to aid in the understanding of the invention, and should notbe construed to limit in any way the invention as defined in the claimswhich follow thereafter.

EXAMPLE 1

Etorphine and Dihydroetorphine Act as Potent Selective Antagonists atExcitatory Opioid Receptors on DRG Neurons Thereby Enhancing InhibitoryEffects of Bimodally-Acting Opioid Agonists

Methods

The experiments described herein were carried out on dorsal rootganglion (DRG) neurons in organotypic explants of spinal cord withattached DRGs from 13-day-old fetal mice after 3 to 5 weeks ofmaturation in culture. The DRG-cord explants were grown oncollagen-coated coverslips in Maximow depression-slide chambers. Theculture medium consisted of 65% Eagle's minimal essential medium, 25%fetal bovine serum, 10% chick embryo extract, 2 mM glutamine and 0.6%glucose. During the first week in vitro the medium was supplemented withnerve growth factor (NGF-7S) at a concentration of about 0.5 μg/ml, toenhance survival and growth of the fetal mouse DRG neurons.

In order to perform electrophysiologic procedures, the culture coverslipwas transferred to a recording chamber containing about 1 ml of Hanks'balanced salt solution (BSS). The bath solution was supplemented with 4mM Ca²⁺ and 5 mM Ba²+ (i.e., Ca, Ba/BSS) to provide a prominent baselineresponse for pharmacological tests. Intracellular recordings wereobtained from DRG perikarya selected at random within the ganglion. Themicropipettes were filled with 3 M KCl (having a resistance of about60-100 megohms) and were connected via a chloridized silver wire to aneutralized input capacity preamplifier (Axoclamp 2A) for current-clamprecording. After impalement of a DRG neuron, brief (2 msec) depolarizingcurrent pulses were applied via the recording electrode to evoke actionpotentials at a frequency of 0.1 Hz. Recordings of the action potentialswere stored on a floppy disc using the P-clamp program (AxonInstruments) in a microcomputer (IBM AT-compatible).

Drugs were applied by bath perfusion with a manually operated, push-pullsyringe system at a rate of 2-3 ml/min. Perfusion of test agents wasbegun after the action potential and the resting potential of the neuronreached a stable condition during >4 minute pretest periods in controlCa, Ba/BSS. Opioid-mediated changes in the APD were consideredsignificant if the APD alteration was >10% of the control value for thesame cell and was maintained for the entire test period of 5 minutes.The APD was measured as the time between the peak of the APD and theinflection point on the repolarizing phase. The following drugs wereused in this and the following Examples: etorphine, diprenorphine andmorphine (gifts from Dr. Eric Simon); dihydroetorphine (gift from Dr.B.-Y. Qin, China and United Biomedical, Inc.); naloxone (Endo Labs);naltrexone, DADLE, dynorphin and other opioid peptides (Sigma).

Opioid alkaloids and peptides were generally prepared as 1 mM solutionsin H₂O and then carefully diluted with BSS to the desiredconcentrations, systematically discarding pipette tips after eachsuccessive 1-10 or 1-100 dilution step to ensure accuracy of extremelylow (fM-pM) concentrations.

Results

Intracellular recordings were made from small- and medium-size DRGneuron perikarya (about 10-30 μm in diameter) which generate relativelylong APDs (greater than 3 msec in Ca/Ba BSS) and which showcharacteristic responsiveness to opioid agonists and other properties ofprimary afferent nociceptive neurons as occur in vivo. Acute applicationof selective inhibitory opioid receptor agonists, e.g., etorphine, tothese DRG neurons shortens the APD in 80-90% of the cells tested,whereas low concentrations of bimodally-acting (excitatory/inhibitory)opioids, e.g., morphine, dynorphin, enkephalins, prolong the APD inthese same cells. Relatively small numbers of large DRG neurons (about30-50 μm in diameter) survive in DRG-cord explants (about 10-20%) andshow much shorter APDs (about 1-2 msec in Ca/Ba BSS), with no clear-cutinflection or “hump” on the falling phase of the spike. The APD of theselarge DRG neurons is not altered by exogenous opioids.

The opioid responsiveness of DRG neurons was analyzed by measuring theopioid-induced alterations in the APD of DRG perikarya. A total of 64DRG neurons, (from 23 DRG-cord explants) were studied for sensitivity toprogressive increases in the concentration of etorphine (n=30) ordihydroetorphine (n=38). Etorphine rapidly and dose-dependentlyshortened the APD in progressively larger fractions of DRG cells atconcentrations from 1 fM (30% of cells; n=26) to 1 uM (80% of cells;n=16) (see FIGS. 2 and 3).

FIG. 2 shows that acute application of low (pM-nM) concentrations ofetorphine to naive DRG neurons elicits dose-dependent,naloxone-reversible inhibitory shortening of the action potentialduration (APD). In contrast, dynorphin (and many other bimodally-actingopioid agonists, e.g., morphine, DADLE) elicit excitatory APDprolongation at these low concentrations (see FIG. 3), which can beselectively blocked by <pM levels of etorphine, as well as bydiprenorphine or naltrexone (see FIGS. 4 and 5). FIG. 2A record 1 showsthe action potential (AP) generated by a DRG neuron in balanced saltsolution containing 5 mM Ca²+ and 5 mM Ba²⁺ (BSS). AP response in thisrecord (and in all records below) is evoked by a brief (2 msec)intracellular depolarizing current pulse. FIG. 2A records 2-5 show thatAPD is not altered by bath perfusion with 1 fM etorphine (Et) but isprogressively shortened in 1 pM, 1 nM and 1 μM concentrations (5 minutetest periods). FIG. 2A record 6 shows that APD returns to control valueafter transfer to BSS (9 minute test). FIG. 2B records 1 and 2 show thatAPD of another DRG neuron is shortened by application of 1 nM etorphine(2 minute test). FIG. 2B record 3 shows that APD returns to controlvalue after transfer to 10 nM naloxone (NLX). FIG. 2B records 4 and 5show that APD is no longer shortened by 1 nM or even 1 μM etorphine whenco-perfused with 10 nM naloxone (5 minute test periods).

FIG. 2C records 1 and 2 show that APD of another DRG neuron is prolongedby application of 3 nM morphine. FIG. 2C record 3 shows that APD returnsto controL value by 5 minutes after washout. FIG. 2C record 4 shows thatapplication of 1 pM etorphine does not alter the APD. FIG. 2C record 5shows that APD is no longer prolonged by 3 nM morphine when co-perfusedwith 1 pM etorphine and instead is markedly shortened to a degree whichwould require a much higher morphine concentration in the absence ofetorphine. Similar. results were obtained by pretreatment with 1 pMdiprenorphine (see FIG. 4), with 1 pM naltrexone (FIG. 5) or 1 pMnaloxone. Records in this and subsequent Figures are from DRG neurons inorganotypic DRG-spinal cord explants maintained for 3-4 weeks inculture.

FIG. 3 shows dose-response curves demonstrating that etorphine (Et) (□)and dihydroetorphine (DHE) (⋄) elicit only inhibitory dose-dependentshortening of the APD of DRG neurons at all concentrations tested(fX-μM). In contrast, dynorphin A (1-13) (Dyn) (×) (as well as morphineand other bimodally-acting opioids) elicits dose-dependent excitatoryAPD prolongation at low concentrations (fM-nM) and generally requiresmuch higher concentrations (about 0.1-1 μM) to shorten the APD, therebyresulting in a bell-shaped dose-response curve. Data were obtained from11 neurons for the etorphine tests, 13 for the DHE tests and 35 for thedynorphin tests; 5, 8 and 9 neurons were tested (as in FIG. 2) with allfour concentrations of etorphine, DHE and dynorphin, respectively (fromfM to μM). For sequential dose-response data on the same neuron, thelowest concentrations (e.g., 1 fM) were applied first.

Dihydroetorphine was even more effective (n=38; FIG. 3). Naloxone (10nM) prevented the etorphine- and dihydroetorphine-induced APD shorteningwhich was previously elicited in the same cells (n=12; FIG. 2B). Thesepotent inhibitory effects of etorphine and dihydroetorphine on DRGneurons at low concentrations are in sharp contrast to the excitatoryAPD-prolonging effects observed in similar tests with morphine and awide variety of mu, delta and kappa opioids. None of the DRG neuronstested with different concentrations of etorphine or dihydroetorphineshowed prominent APD prolongation.

The absence of excitatory APD-prolonging effects of etorphine anddihydroetorphine on DRG neurons could be due to low binding affinity ofthese opioid agonists to excitatory opioid receptors. Alternatively,these opioids might bind strongly to excitatory receptors, but fail toactivate them, thereby functioning as antagonists. In order todistinguish between these two modes of action, DRG neurons werepretreated with etorphine at low concentrations (fM-pM) that evokedlittle or no alteration of the APD. subsequent addition of nMconcentrations of morphine, DAGO, DADLE or dynorphin toetorphine-treated cells no longer evoked the usual APD prolongationobserved in the same cells prior to exposure to etorphine (n=11; seeFIG. 2C). This etorphine-induced blockade of opioid excitatory effectson DRG neurons was often effective for periods up to 0.5-2 hours afterwashout (n=4).

These results demonstrate that etorphine, which has been considered tobe a “universal” agonist at mu, delta and kappa opioid receptors (seeMagnan et al., Naunyn-Schmiedeberg's Arch. Pharmacol., Vol. 319, pp.197-205 (1982)), has potent antagonist actions at mu, delta and kappaexcitatory opioid receptors on DRG neurons, in addition to itswell-known agonist effects at inhibitory opioid receptors. Pretreatmentwith dihydroetorphine (fM-pM) showed similar antagonist action atexcitatory opioid receptor mediating nM opioid-induced APD prolongation(n=2). Furthermore, after selective blockade of opioid excitatoryAPD-prolonging effects by pretreating DRG neurons with lowconcentrations of etorphine (fM-pM), which showed little or noalteration of the APD, fM-nM levels of bimodally-acting opioids nowshowed potent inhibitory APD-shortening effects (5 out of 9 cells) (seeFIG. 2C and FIG. 4). This is presumably due to unmasking of inhibitoryopioid receptor-mediated functions in these cells after selectiveblockade of their excitatory opioid receptor functions by etorphine.

EXAMPLE 2

Diprenorphine, Naloxone and Naltrexone, at Low Concentrations, Also ShowPotent Selective Antagonist Action at Excitatory opioid Receptors

Drug Tests

Mouse DRG-cord explants, grown for >3 weeks as described in Example 1,were tested with the opioid antagonists diprenorphine, naltrexone andnaloxone. Electrophysiological recordings were made as in Example 1.

Results

The opioid receptor antagonists naloxone and diprenorphine werepreviously shown to black, at nM concentrations, both inhibitory APDshortening of DRG neurons by μM opioid agonists as well as excitatoryAPD prolongation by nM opioids. Tests at lower concentrations haverevealed that pM diprenorphine, as well as pM naloxone or naltrexone,act selectively as antagonists at mu, delta and kappa excitatory opioidreceptors, comparable to the antagonist effects of pM etorphine anddihydroetorphine. In the presence of pM diprenorphine, morphine (n=7)and DAGO (n=7). no longer elicited APD prolongation at low (pM-nM)concentrations (see FIG. 4A). Instead, they showed progressivedose-dependent APD shortening throughout the entire range ofconcentrations from fM to μM (see FIG. 4B), comparable to thedose-response curves for etorphine and dihydroetorphine (see FIG. 3 andFIG. 2C). This unmasking of inhibitory opioid receptor-mediatedADP-shortening effects by pM diprenorphine occurred even in the presenceof 10-fold higher concentrations of morphine (see FIG. 4A, records 11vs. 5).

FIG. 4 shows that excitatory APD-prolonging effects elicited by morphinein DRG neurons are selectively blocked by co-administration of a low(pM) concentration of diprenorphine, thereby unmasking potentdose-dependent inhibitory APD shortening by low concentrations ofmorphine. FIG. 4A records 1-4 show that APD of a DRG neuron isprogressively prolonged by sequential bath perfusions with 3 fM, 3 pMand 3 μM morphine (Mor). FIG. 4A record 5 shows that APD of this cell isonly slightly shortened after increasing morphine concentration to 3 pM.FIG. 4A records 6 and 7 show that after transfer to 355, the APD isslightly shortened during pretreatment for 17 minutes with 1 pMdiprenorphine (DPN). FIG. 4A records 8-11 show that after the APDreached a stable value in DPN, sequential applications of 3 fM, 3 pM, 3nM and 3 μM Mor progressively shorten the APD, in contrast to the markedAPD prolongation evoked by these same concentrations of Mor in theabsence of DPN (see also FIG. 2C). FIG. 4B dose-response curvesdemonstrate similar unmasking by 1 pM DPN of potent dose-dependentinhibitory APD shortening by morphine (□) in a group of DRG neurons(n=7), all of which showed only excitatory APD prolongation responseswhen tested prior to introduction of DPN (X). Note that the inhibitorypotency of morphine in the presence of pM DPN becomes comparable to thatof etorphine and dihydroetorphine (see FIG. 3). In contrast,pretreatment with a higher (nM) concentration of DPN blocks bothinhibitory as well-as excitatory effects of morphine ().

FIG. 5 shows that excitatory APD-prolonging eeffects elicited bymorphine in DRG neurons (∘) are also selectively blocked byco-administration of a low (pM) concentration of naltrexone (NTX),thereby unmasking-potent dose-dependent inhibitory APD shortening by lowconcentrations or morphine (X). In contrast, pretreatment with a higher(μM) concentration of NTX blocks both inhibitory as well as excitatoryeffects of morphine (□) (similar blockade occurs with 1 nM NTX). Thesedose-response curves are based on data from 18 neurons, all of whichshowed only excitatory APD prolongation responses when tested prior tointroduction of NTX. The inhibitory potency of morphine in the presenceof pM NTX becomes comparable to that of etorphine and dihydroetorphine(see FIG. 3).

EXAMPLE 3

Chronic Co-treatment of DRG Neurons With Morphine and Ultra-low-doseNaloxone or Naltrexone Prevents Development of Opioid ExcitatorySupersensitivity (“Dependence”) and Tolerance

Co-administration of ultra-low (pM) concentrations of naloxone ornaltrexone during chronic treatment of DRG neurons with μM levels ofmorphine was effective in preventing development of opioid excitatorysupersensitivity and tolerance which generally occurs after sustainedexposure to bimodally-acting opioids. Acute application of fM dynorphinA-(1-13) or fM morphine (n=21), as well as 1 nM naloxone (n=11), to DRGneurons chronically exposed to 1 μM morphine together with 1 pM naloxoneor naloxone or naltrexone (for 1-10 weeks) did not evoke the usualexcitatory APD prolongation observed in chronic morphine-treated cellstested after washout with BSS (see FIG. 6). Furthermore, there was noevidence of tolerance to the usual inhibitory effects of μM opioids(n=6) (FIG. 6).

These results are consonant with previous data that blockade ofsustained opioid excitatory effects by cholera toxin-B sub-unit duringchronic morphine treatment of DRG neurons prevents development oftolerance and dependence. (see Shen and Crain, Brain Res., Vol. 597, pp.74-83 (1992)). This toxin sub-unit selectively interferes with GM1ganglioside regulation of excitatory opioid receptor functions (see Shenand Crain, Brain Res., Vol. 531, pp. 1-7 (1990) and Shen et al., BrainRes., Vol. 559, pp. 130-138 (1991)).

Similarly, in the presence of pM etorphine, chronic μM morphine-treatedDRG neurons did not develop signs of tolerance or dependence. FIG. 6outlines the assay procedure used for testing the effectiveness of theseand other antagonists at excitatory opioid receptors in preventingdevelopment of tolerance/dependence during chronic co-treatment of DRGneurons with morphine.

EXAMPLE 4

Excitatory Opioid Receptor Antagonists Enhance Analgesic Potency andReduce Dependence Liability and Other Side Effects of Morphine WhenAdministered in Combination With Morphine

Electrophysiological studies on DRG neurons in culture indicated thatpretreatment with low fM-pM concentrations of naltrexone, naloxone,diprenorphine, etorphine or dihydroetorphine is remarkably effective inblocking excitatory APD-prolonging effects of morphine or otherbimodally-acting opioid agonists by selective antagonist actions at mu,delta and kappa excitatory opioid receptors on these cells. In thepresence of these selective excitatory opioid receptor antagonists,morphine and other clinically used bimodally-acting opioid agonistsshowed markedly increased potency in evoking the inhibitory effects onthe action potential of sensory neurons which are generally consideredto underlie opioid analgesic action in vivo.

These bimodally-acting opioid agonists became effective in shortening,instead of prolonging, the APD at pM-nM (i.e., 10⁻¹²-10⁻⁹ M)concentrations, whereas 0.1-1 μM (i.e., 10⁻⁷-10⁻⁶ M) levels weregenerally required to shorten the APD (FIGS. 4B and 5). Selectiveblockade of the excitatory side effects of these bimodally-acting opioidagonists eliminates the attenuation of their inhibitory effectivenessthat would otherwise occur. Hence, according to this invention, thecombined use of a relatively low dose of one of these selectiveexcitatory opioid receptor antagonists, together with morphine or otherbimodally-acting mu, delta or kappa opioid agonists, will markedlyenhance the analgesic potency of said opioid agonist, and render saidopioid agonist comparable in potency to etorphine or dihydroetorphine,which, when used alone, are >1000 times more potent than morphine ineliciting analgesia.

Co-administration of one of these excitatory opioid receptor antagonistsat low (pM) concentration (10⁻¹² M) during chronic treatment of sensoryneurons with 10⁻⁶ M morphine or other bimodally-acting opioid agonists(>1 week in culture) prevented development of the opioid excitatorysupersensitivity, including naloxone-precipitated APD-prolongation, aswell as the tolerance to opioid inhibitory effects that generally occursafter chronic opioid exposure. This experimental paradigm was previouslyutilized by the inventors on sensory neurons in culture to demonstratethat co-administration of 10⁻⁷ M cholera toxin-B sub-unit, which bindsselectively to GM1 ganglioside and thereby blocks excitatoryGM1-regulated opioid receptor-mediated effects, but not opioidinhibitory effects (see Shen and Crain, Brain Res., Vol. 531, pp. 1-7(1990)), during chronic opioid treatment prevents development of theseplastic changes in neuronal sensitivity that are considered to becellular manifestations related to opioid dependence/addiction andtolerance in vivo (see Shen and Crain, Brain Res., Vol. 597, pp. 74-83(1992)).

EXAMPLE 5

Cotreatment of Mice With Morphine Plus Ultra Low Dose NaltrexoneEnhances Opioid Antinociceptive Potency

Antinociceptive effects of opioids were measured using a warm-water tailflick assay similar to methods described in Horan, P. J., et al. J.Pharmacol. Exp. Ther. 264:1446-1454 (1993). In this regard, each mousewas inserted into a plastic restraining device that permitted the tailto be dipped into a water bath maintained at 55° C. The latency to arapid tail flick was recorded; mice with control latencies >5 secondswere excluded from these tests and a 10 second cutoff was used tominimize tissue damage. Six sequential control tests were made, eachwith a 10 minute interval. The latencies of the last four tests wereaveraged to provide a control value. Percent antinociception wascalculated according to the formula: 100×[(test latency−controllatency)/10−control latency)]. Differences between treatment groups wereexamined for statistical significance by means of ANOVA withNeuman-Keuls tests.

Untreated mice showed tail-flick latencies of 2.15±0.4 seconds (mean±SD;n=58). Cotreatment of mice with 10 mg of morphine per kg plus a1000-fold lower dose of naltrexone (10 μg/kg, i.p.) resulted in moderateattenuation and no significant enhancement of the analgesic potency ofmorphine injected alone. In contrast, cotreatment of mice with 1 mg ofmorphine per kg plus a 100,000 fold lower dose of naltrexone (10 ng/kg,i.p.) demonstrated that in the presence of this extremely low dose ofnaltrexone, the peak values of tail-flick latencies at 1 hour weremaintained during the subsequent hour, whereas the antinociceptiveeffects of morphine alone rapidly decreased during this same period.Furthermore, a remarkable degree of antinociception was maintainedfor >1.5 hours after the effects of 1 mg of morphine per kg alone wereno longer detectable (n=25; FIG. 7). The marked enhancement of theanalgesic potency of morphine in mice during cotreatment with 10 ng ofnaltrexone per kg is quite consonant with the unmasking of potentinhibitory effects of 1 pM-1 nM morphine in DRG neurons in vitro bycotreatment with 1 pM naltrexone.

EXAMPLE 6

Cotreatment of Mice With Morphine Plus Low-Dose Naltrexone AttenuatesWithdrawal Jumping Behavior Acute Physical Dependence Assays

Acute physical dependence was assessed by recordingnaloxone-precipitated withdrawal jumping behavior in mice that had beeninjected 3-4 hours earlier with a 100 mg/kg (s.c.) dose of morphine(Horan, P. J., et al. supra; Yano, I. and Takemori, A. E. Res. Commun.Chem. Pathol. Pharmacol. 16:721-733 (1977); Sofuoglu, M., et al. J.Pharmacol. Exp. Ther. 254:841-846 (1990), administered alone or togetherwith a low dose of naltrexone. Each mouse was placed individually in atall container and the number of abrupt, stereotyped jumps was recordedduring a 15 minute period after administration of naloxone (10 mg/kg,i.p.). Differences between treatment groups were examined forstatistical significance by means of X² tests.

Three to four hours after the administration of a high dose of morphine(100 mg/kg, s.c.), injection of naloxone (10 mg/kg, i.p.) evokedcharacteristic withdrawal jumping behavior. About 67% of these treatedmice (n=30) showed 5-100 robust jumps during a 15 minute test period(n=30; FIG. 8), whereas jumping behavior was observed in only 10-20% ofuntreated mice. On the other hand, after cotreatment of mice with a10,000-fold lower dose of naltrexone (10 μg/kg) administered 15 minutesprior to and together with 100 mg of morphine per kg, the incidence ofnaloxone-precipitated jumping behavior was markedly reduced to only 23%of the treated animals (n=30); FIG. 8). The mice were routinelypretreated with naltrexone to ensure antagonist binding to excitatoryopioid receptors prior to their possible long-lasting activation bymorphine. An additional injection of naltrexone (10 μg/kg, s.c.) wasmade 2 hours after administration of morphine plus naltrexone, becausethis antagonist has been reported to have a much shorter duration ofaction in mice, in contrast to humans.

Antinociceptive tail-flick tests on naive mice were made in order toshow that this effect of 10 μg of naltrexone per kg was mediatedprimarily by blocking excitatory, rather than inhibitory, opioidreceptor functions. Cotreatment of mice with 100 mg of morphine per kgplus 10 μg of naltrexone per kg (i.p.) did not significantly attenuatethe potent (supramaximal) analgesic effect of 100 mg of morphine per kginjected alone. In both groups of treated mice, tail-flick latenciesrapidly increased to the peak cutoff value of 10 seconds.

Chronic Physical Dependence and Tolerance Assays

Chronic physical dependence was assessed by similarnaloxone-precipitated withdrawal jumping behavior tests as describedabove in mice that had been injected for four days (twice daily) withincreasing doses of morphine (20-50 mg/kg, s.c.), alone or together witha low dose of naltrexone. On the fifth day, the animals were primed withmorphine (10 mg/kg) and challenged 1 hour later with naloxone (10 mg/kg,i.p.), as in previous chronic morphine-dependence assays (Sofuoglu, M.,et al. J. Pharmacol. Exp. Ther. 254:841-846 (1990); Brase, D. B., et al.J. Pharmacol. Exp. Ther. 197:317-325 (1976); Way, E. L. and Loh, H. H.Ann. N.Y. Acad. Sci. 281:252-261 (1976)). Differences between treatmentgroups were examined for statistical significance by means of X² tests.

About 60% of the treated mice showed stereotyped jumping as observed inthe acute dependence tests (n=30; FIG. 8). By contrast, aftercotreatment of mice with 10 μg of naltrexone per kg (s.c.) administered15 minutes prior to and together with each of the morphine injectionsindicated above, naloxone-precipitated jumping occurred in only 13% ofthe mice (n=30; FIG. 8). Tail-flick assays on naive mice showed thatcotreatment with 20 mg of morphine per kg plus 10 μg of naltrexone perkg did not significantly attenuate the analgesic effect of 20 mg ofmorphine per kg injected alone. In similar-chronic cotreatment testsusing a 10-fold lower dose of naltrexone (1 μg/kg), withdrawal jumpingwas still markedly attenuated from 60% down to 30% of the mice (n=30;data not shown). These results demonstrate that, chronic cotreatmentwith morphine plus 50,000- to 5,000-fold lower doses of naltrexonesignificantly decreased development of physical dependence.

Tail-flick assays on some of these chronic cotreated mice at 1 day afterdrug withdrawal showed that opioid tolerance was also partiallyattenuated. Acute injection of 1 mg of morphine per kg resulted in amuch larger degree of antinociception in chronic morphine plus 10 ng ofnaltrexone per kg cotreated mice (15%±3%, n=10; time to peak effect at30 minutes), as compared to chronic morphine-treated mice (3%±2% at 30minutes, n=10; peak effect of 7%±1$ at 60 minutes) (data not shown).

EXAMPLE 7

Cotreatment of Mice With Morphine Plus Low-Dose Nalmefene EnhancesOpioid Antinociceptive Potency

Mice were injected (i.p.) with 3 mg/kg morphine alone, and 3 mg/kgmorphine in combination with 30,000-fold lower dose of nalmefene (100ng/kg, i.p.), 300,000-fold lower dose of nalmefene (10 ng/kg, i.p.) and3,000,000-fold lower dose of nalmefene (1 ng/kg, i.p.). Ten mice wereused per dosing group. Antinociceptive effects of opioids were measuredusing a warm-water tail f-lick assay as described above. The results arepresented in FIG. 9. Co-treatment of mice with ultra-low doses ofnalmefene (NLF) enhances morphine's antinociceptive potency, in contrastto the characteristic attenuation of morphine analgesia by higher dosesof nalmefene. Co-treatment with 1 ng/kg nalmefene was as effective as 10ng/kg naltrexone in enhancing morphine antinociceptive potency (compareFIGS. 7 and 9).

EXAMPLE 8

Cotreatment of Mice With Morphine Plus Low-Dose Nalmefene AttenuatesWithdrawal Jumping Behavior Acute Physical Dependence Assays

Mice were injected with a 100 mg/kg (s.c.) dose of morphine,administered either alone or in combination with 1 or 10 μg/kg (s.c.)dose of nalmefene or 10 μg/kg (s.c.) dose of naltrexone (as control),followed by additional injections of nalmefene (1 or 10 μg/kg, s.c.) ornaltrexone (10 μg/kg, s.c.) 90 minutes after the initial injections.Acute physical dependence was assessed by recordingnaloxone-precipitated withdrawal jumping behavior in mice 4 hours afterthe initial injections. The results are presented in FIG. 10.Co-treatment of mice for 4 hours with morphine plus the low dosenalmefene (NLF; n=40) or naltrexone (NTX; n=30) attenuatesnaloxone-precipitated withdrawal-jumping in the acute physicaldependence assays. These results demonstrate that co-treatment withnalmefene is as effective as naltrexone in attenuating morphinedependence liability. Tests with 1 μg/kg nalmefene (n=10) indicate thatnalmefene may even be more effective than naltrexone in attenuatingmorphine dependence liability.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of various aspects of the invention. Thus, it isto be understood that numerous modifications may be made in theillustrative embodiments and other arrangements may be devised withoutdeparting from the spirit and scope of the invention.

What is claimed is:
 1. A method for selectively enhancing the analgesicpotency of a bimodally-acting opioid agonist and simultaneouslyattenuating anti-analgesia, hyperalgesia, hyperexcitability, physicaldependence and/or tolerance effects associated with the administrationof said bimodally-acting opioid agonist, comprising administering to asubject an analgesic or sub-analgesic amount of a bimodally-actingopioid agonist selected from the group consisting of morphine, codeine,fentanyl analogs, buprenorphine, methadone, enkephalins, dynorphins, andendorphins, and an amount of an excitatory opioid receptor antagonistselected from the group consisting of naloxone and naltrexone effectiveto enhance the analgesic potency of said bimodally-acting opioid agonistand attenuate the anti-analgesia, hyperalgesia, hyperexcitability,physical dependence and/or tolerance effects of said bimodally-actingopioid agonist.
 2. The method of claim 1, wherein the amount of theexcitatory opioid receptor antagonist administered is at least 100-1000times less than the amount of the bimodally-acting opioid agonist. 3.The method of claim 1, wherein the bimodally-acting opioid agonist ismorphine.
 4. The method of claim 1, wherein the bimodally-acting opioidagonist is codeine.
 5. The method of claim 1, wherein thebimodally-acting opioid agonist is methadone.
 6. The method of claim 1,wherein the excitatory opioid receptor antagonist is naloxone.
 7. Themethod of claim 1, wherein the excitatory opioid receptor antagonist isnaltrexone.
 8. The method of claim 1, wherein the mode of administrationis selected from the group consisting of oral, sublingual,intramuscular, subcutaneous and intravenous administration.
 9. A methodfor treating pain in a subject comprising administering to said subjectan analgesic or sub-analgesic amount of a bimodally-acting opioidagonist selected from the group consisting of morphine, codeine,fentanyl analogs, buprenorphine, methadone, enkephalins, dynorphins, andendorphins, and an amount of an excitatory opioid receptor antagonistselected from the group consisting of naloxone and naltrexone effectiveto enhance the analgesic potency of said bimodally-acting opioid agonistand attenuate the anti-analgesia, hyperalgesia, hyperexcitability,physical dependence and/or tolerance effects of said bimodally-actingopioid agonist.
 10. The method of claim 9, wherein the amount of theexcitatory opioid receptor antagonist administered is at least 100-1000times less than the amount of the bimodally-acting opioid agonist. 11.The method of claim 9, wherein the bimodally-acting opioid agonist ismorphine.
 12. The method of claim 9, wherein the bimodally-acting opioidagonist is codeine.
 13. The method of claim 9, wherein thebimodally-acting opioid agonist is methadone.
 14. The method of claim 9,wherein the excitatory opioid receptor antagonist is naloxone.
 15. Themethod of claims 9, wherein the excitatory opioid receptor antagonist isnaltrexone.
 16. The method of claim 9, wherein the mode ofadministration is selected from the group consisting of oral,sublingual, intramuscular, subcutaneous and intravenous administration.17. A method for detoxifying and treating an opiate addict comprisingadministering to the opiate addict an analgesic or sub-analgesic amountof a bimodally-acting opioid agonist selected from the group consistingof morphine, codeine, fentanyl analogs, buprenorphine, methadone,enkephalins, dynorphins, and endorphins, and an amount of an excitatoryopioid receptor antagonist selected from the group consisting ofnaloxone and naltrexone effective to enhance the analgesic potency ofsaid bimodally-acting opioid agonist and attenuate the anti-analgesia,hyperalgesia, hyperexcitability, physical dependence and/or toleranceeffects of said bimodally-acting opioid agonist, thereby detoxifying andtreating said opiate addict.
 18. The method of claim 17, wherein thebimodally-acting opioid agonist is methadone.
 19. The method of claim17, wherein the excitatory opioid receptor antagonist is naltrexone. 20.The method of claim 17, wherein the excitatory opioid receptorantagonist is naloxone.
 21. The method of claim 17, wherein thebimodally acting opioid agonist is methadone and the excitatory opioidreceptor antagonist is naloxone.
 22. The method of claim 17, wherein thebimodally acting opioid agonist is methadone and the excitatory opioidreceptor antagonist is naltrexone.
 23. The method of claim 17, whereinthe mode of administration is selected from the group consisting oforal, sublingual, intramuscular, subcutaneous and intravenousadministration.
 24. A composition comprising an analgesic orsub-analgesic amount of a bimodally-acting opioid agonist selected fromthe group consisting of morphine, codeine, fentanyl analogs,buprenorphine, methadone, enkephalins, dynorphins, and endorphins, andan amount of an excitatory opioid receptor antagonist selected from thegroup consisting of naloxone and naltrexone effective to enhance theanalgesic potency of said bimodally-acting opioid agonist and attenuatethe anti-analgesia, hyperalgesia, hyperexcitability, physical dependenceand/or tolerance effects of said bimodally-acting opioid agonist. 25.The composition of claim 24, wherein the amount of the excitatory opioidreceptor antagonist administered is at least 100-1000 times less thanthe amount of the bimodally-acting opioid agonist.
 26. The compositionof claim 24, wherein the bimodally-acting opioid agonist is morphine.27. The composition of claim 24, wherein the bimodally-acting opioidagonist is codeine.
 28. The composition of claim 24, wherein thebimodally-acting opioid agonist is methadone.
 29. The composition ofclaim 24, wherein the excitatory opioid receptor antagonist is naloxone.30. The composition of claim 24, wherein the excitatory opioid receptorantagonist is naltrexone.
 31. A method for selectively enhancing theanalgesic potency of a bimodally-acting opioid agonist andsimultaneously attenuating anti-analgesia, hyperalgesia,hyperexcitability, physical dependence and/or tolerance effectsassociated with the administration of said bimodally-acting opioidagonist, comprising administering to a subject an analgesic orsub-analgesic amount of a bimodally-acting opioid agonist selected fromthe group consisting of morphine, codeine, fentanyl analogs,buprenorphine, methadone, enkephalins, dynorphins, and endorphins, andan amount of an excitatory opioid receptor antagonist effective toenhance the analgesic potency of said bimodally-acting opioid agonistand attenuate the anti-analgesia, hyperalgesia, hyperexcitability,physical dependence and/or tolerance effects of said bimodally-actingopioid agonist.